Patient-Derived Antibody Data Yields Development of Broadly Cross-Protective Monoclonal Antibody against ST258 Carbapenem-Resistant Klebsiella pneumoniae

Abstract

ABSTRACT The most pressing challenge for the development of anti-capsular antibodies is maximizing coverage against the heterogenous capsular polysaccharide (CPS) of carbapenem-resistant Klebsiella pneumoniae (CR-Kp). So far, only CR-Kp with wzi154 CPS has been successfully targeted by antibodies. Here, we present murine antibody 24D11, which was developed by vaccinating mice with purified wzi50-type CPS. Cross-reactivity and protective efficacy of MAb 24D11 were confirmed against CR-Kp that express the 3 most prevalent CPS types (wzi29, wzi154, wzi50) using both in vitro and in vivo infection models. 24D11 induced complement-mediated and independent opsonophagocytosis in macrophages as well as killing of all CR-Kp strains in whole blood cells derived from healthy donors. In a murine intratracheal infection model, 24D11 reduced lung burden and dissemination of CR-Kp strains when administered 4 h pre- or postinfection. The protective efficacy of 24D11 remained effective in neutropenic mice. This is the first antibody which exhibits cross-protective efficacy against clade 1 and 2 ST258 CR-Kp strains. It overcomes a major barrier to successfully target wzi29, a major CPS expressed by ST258 CR-Kp. The finding that 24D11 also exhibits potent protective efficacy against wzi154 CR-Kp strains highlights its high potential as a lead agent for the development of broadly active immunotherapy. IMPORTANCE Here, we present in vitro and in vivo data for the wzi50 CPS-specific monoclonal antibody MAb 24D11, demonstrating its cross-protective efficacy against three prominent win types (wzi29, wzi154, and wzi50) of the carbapenem-resistant clonal group CG258. In a murine pulmonary infection model, MAb 24D11 reduced bacterial lung burden and dissemination to other organs even if administered 4 h postinfection. Its protective efficacy was also observed in neutropenic mice, which highlights its potential value in clinical settings where oncology patients with CG258 infections may also be neutropenic.

Keywords

• carbapenem-resistant Klebsiella pneumoniae
• ST258
• anti-bacterial immunotherapy
• capsular antibodies
• cross-protection
• capsular polysaccharide